Exploring the synergy between tumor microenvironment modulation and STING agonists in cancer immunotherapy DOI Creative Commons
Xiaoyan Qi, Cheng Cheng, Dawei Zhang

и другие.

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Дек. 6, 2024

Cancer immunotherapy has revolutionized the treatment of various malignancies, particularly with advent immune checkpoint inhibitors and CAR-T cell therapies [1][2][3]. These approaches have yielded impressive outcomes in a subset patients, yet many still fail to achieve durable responses [4]. One key reasons for this disparity is presence an immunosuppressive tumor microenvironment (TME), which plays crucial role limiting effectiveness immune-based [5,6]. The TME comprises complex network cellular molecular components, including tumor-associated macrophages (TAMs), regulatory T cells (Tregs), myeloid-derived suppressor (MDSCs), all contribute evasion progression [7][8][9].The STING (stimulator interferon genes) pathway emerged as promising target cancer due its ability bridge innate adaptive [10,11]. Upon activation by cytosolic DNA, triggers production type I interferons other pro-inflammatory cytokines, leading dendritic (DCs) subsequent priming [12]. This process initiating robust anti-tumor response.However, despite potential agonists stimulate powerful responses, their efficacy clinical settings been limited, primarily nature TME, can dampen initiated [13]. TAMs, Tregs, MDSCs, together hostile environment that inhibits effective responses.TAMs often adopt M2-like phenotype within characterized anti-inflammatory tissue-remodeling activities promote growth suppress [14]. Recent studies shown lead shift TAM polarization from M2 M1, enhancing secretion cytokines such TNF-α IL-12, are immunity. Tregs play dual maintaining homeostasis but hinder immunity inhibiting cytotoxic functions. Targeting through may decrease suppressive effects, allowing more response against [15].MDSCs represent significant barrier successful produce reactive oxygen species (ROS) factors inhibit activation.Emerging evidence suggests reduce MDSC levels or impair function, thereby alleviating suppression activity [16,17]. extracellular matrix (ECM) physical characteristics hypoxia acidosis, also suppression. enhance remodeling ECM, facilitating better infiltration improving therapeutic [18].Given these challenges, there growing interest exploring synergistic combination strategies not only modulate overall [19,20]. For instance, targeting specific components suppression, create favorable STING-mediated [21,22]. demonstrated combining like bispecific antibodies leads enhanced improved regression. approach great promise overcoming resistance mechanisms associated current immunotherapies. By leveraging multiple modalities, researchers aim ultimately patient [23]. article will delve into immunotherapy, how modulation treatments. uniquely contributes field systematically evaluating combined TME-modulating therapies, overlooked literature. Moreover, it emphasizes critical need personalized consider distinct individual microenvironments, optimizing efficacy. Additionally, manuscript outlines future research directions elucidate interacts paving way innovative applications. Unlike previous focus on isolated interventions, provides comprehensive overview diverse TME-targeting significantly optimize improve outcomes.TME dynamic entity [24,25]. It consists cells, fibroblasts, endothelial ECM [26]. Among MDSCs players [7][8][9].TAMs [27]. secrete IL-10 TGF-β, proliferation natural killer (NK) fostering protects attack [28]. another component functioning maintain tolerance prevent autoimmunity. However, context cancer, effector secreting TGF-β. escape them proliferate unchecked [29]. heterogeneous population immature myeloid expand during chronic inflammatory conditions. Within function ROS, nitric oxide (NO), arginase, further contributing [30]. present challenges immunotherapy. creates barriers, dense impede agents tumor. hypoxic acidic conditions commonly found exacerbate therapy [31].In addition previously discussed non-cellular roles. Endothelial line blood vessels, essential supplying nutrients [32]. they overexpress adhesion molecules chemokines, attracting thus suppressing anti -tumor cells. Their abnormal vessel structure impairs drug delivery favors survival metastasis [33].Stroma especially creating fibrotic restricts [34,35]. They affecting cells' behavior, understanding crosstalk devising agonists.Tumor root problem, downregulate MHC expression, TGF -β IL -10, undergo alterations [36]. A interactions developing those integrating agonists, outcomes.Addressing requires restore be possible reprogram state one supports immunity, immunotherapy.The system, playing pivotal detecting originates viral infections damaged cells.Upon recognition cyclic GMP-AMP synthase (cGAS) enzyme produces (cGAMP), second messenger directly activates protein [37].Once activated, translocates endoplasmic reticulum Golgi apparatus, where signaling cascade phosphorylation factor 3 (IRF3) (IFNs) [38].Type IFNs, IFN-α IFN-β, bridging responses. activate DCs, antigen presentation, lymphocytes (CTLs), destroying [39]. makes attractive initiate capable TME. Preclinical induce potent tumors. convert "cold" tumors-those low infiltration-into "hot" tumors responsive In promoting infiltration, direct induction death certain types, control [40]. translation encountered challenges. activation, when used monotherapy [41]. Furthermore, systemic administration carries risk inducing excessive inflammation, toxicity [42]. To overcome increasing strategies, [43]. Such immune-stimulating effects while mitigating influences maximizing immunotherapy.TME determining success failure As highly milieu, recruited interventions. poses challenge rely exert effects. Therefore, [44,45].One primary modulating tumors, pro-tumoral [46]. Reprogramming TAMs M1 agonists. M1-like support macrophage burden making permissive induced [47].In approach. reducing number enhanced. Combining Treg depletion could stronger sustained [48].MDSCs ROS NO, among [49]. Reducing blocking alleviate major barriers When MDSC-targeting removing source [50].As we explored ways becomes evident aspects require attention. -angiogenic normalizes vasculature, agonist [51,52].Engineering using drugs -promoting surface, molecule expression transmigration, boost [53]. Regarding stroma multi -pronged viable. Inhibiting overproduction degradation, cytokine/growth -induced [54]. include upregulating secretion, genetic/epigenetic alterations. approaches, efficacy.Beyond Strategies normalize alter metabolic facilitate example, stiffness penetration both [55]. synergy between preclinical models, compared either alone. reprogramming immunologically active, likelihood eradication [10]. summarize please refer Table 1. conclusion, represents strategy resistant ones, offering new hope patients who do respond modalities.As area progresses, identify most combinations application maximize outcomes. Figure 1 illustrates elements microenvironment, pathway, described section. advancements [56]. proinflammatory immunity.However, monotherapies limited result, trials focused [57].One notable involves ADU-S100, results pembrolizumab, PD-1 inhibitor, advanced solid [58]. led increased higher rate, suggesting inhibitors, immune-modulating anti-CTLA-4antibodies [59,60]. DMXAA anti-CTLA-4 murine models resulted complete regression some cases, highlighting approaches.In mentioned novel agent MSA -2 candidate non -CDN bioactivity. investigations, remarkable potential. cervical -PD -1, efficacy.This [61]. involving -β/PD -L1 antibody, exhibited [62].These findings suggest valuable arsenal potentially avenues treating malignancies outcomes.In order enrich landscape several related emerged. TAK -676, developed Takeda, promise.In robustly increase production. This, turn, holds addresses converting ones treatment. Clinically, offers tool existing therapies. across different inflammation must carefully managed. Future should TMEs, targeted systems minimizing side effects.This integrated

Язык: Английский

Innovations in Antibody-Drug Conjugate (ADC) in the Treatment of Lymphoma DOI Open Access
Ali Al Sbihi, Maryam Alasfour, Georgios Pongas

и другие.

Cancers, Год журнала: 2024, Номер 16(4), С. 827 - 827

Опубликована: Фев. 18, 2024

Chemoimmunotherapy and cellular therapy are the mainstay of treatment relapsed/refractory (R/R) lymphomas. Development resistance commonly encountered toxicities these treatments limit their role in achieving desired response rates durable remissions. The Antibody–Drug Conjugate (ADC) is a novel class targeted that has demonstrated significant efficacy treating various cancers, including To date, three ADC agents have been approved for different lymphomas, marking advancement field. In this article, we aim to review concept ADCs application lymphoma treatment, provide an analysis currently agents, discuss ongoing advancements development.

Язык: Английский

Процитировано

7

Genomic Features of Homologous Recombination Deficiency in Breast Cancer: Impact on Testing and Immunotherapy DOI Open Access

Umer Ali,

Sunitha Vungarala,

Venkataswarup Tiriveedhi

и другие.

Genes, Год журнала: 2024, Номер 15(2), С. 162 - 162

Опубликована: Янв. 26, 2024

Genomic instability is one of the well-established hallmarks cancer. The homologous recombination repair (HRR) pathway plays a critical role in correcting double-stranded breaks (DSB) due to DNA damage human cells. Traditionally, BRCA1/2 genes HRR have been tested for their association with breast However, defects (HRD, also termed 'BRCAness'), which has up 50 genes, shown be involved tumorigenesis and treatment susceptibility poly-ADP ribose polymerase inhibitors (PARPis), platinum-based chemotherapy, immune checkpoint (ICIs). A reliable consensus on HRD scores yet established. Emerging evidence suggests that only subset cancer patients benefit from ICI-based immunotherapy. Currently, albeit limitations, expression programmed death-ligand 1 (PDL1) tumor mutational burden (TMB) are utilized as biomarkers predict favorable outcomes ICI therapy patients. Preclinical studies demonstrate an interplay between PDL1 expression. In this review, we outline current understanding genomic leading delineate various clinical trials. Furthermore, discuss potential strategies combining HRD-targeted immunotherapy achieve best healthcare

Язык: Английский

Процитировано

5

Nuclear localization of heparanase 2 (Hpa2) attenuates breast carcinoma growth and metastasis DOI Creative Commons

Maram Hilwi,

K. Shulman,

Inna Naroditsky

и другие.

Cell Death and Disease, Год журнала: 2024, Номер 15(3)

Опубликована: Март 22, 2024

Abstract Unlike the intense research effort devoted to exploring significance of heparanase in cancer, very little attention was given Hpa2, a close homolog heparanase. Here, we explored role Hpa2 breast cancer. Unexpectedly, found that patients endowed with high levels exhibited higher incidence tumor metastasis and survived less than low Hpa2. Immunohistochemical examination revealed normal tissue, localizes primarily cell nucleus. In striking contrast, carcinoma, expression is not only decreased but also loses its nuclear localization appears diffuse cytoplasm. Importantly, cancer which retained reduced lymph-node metastasis, suggesting plays protective progression. To examine this possibility, engineered gene construct directs nucleus (Hpa2-Nuc). Notably, overexpression carcinoma cells resulted bigger tumors, whereas targeting attenuated growth metastasis. RNAseq analysis performed reveal differentially expressed genes (DEG) Hpa2-Nuc tumors vs. control. The revealed, among others, associated hallmark Kras, beta-catenin, TNF-alpha (via NFkB) signaling. Our results imply prominently regulates transcription, resulting attenuation tumorigenesis. Thus, may be used as predictive parameter personalized medicine for patients.

Язык: Английский

Процитировано

4

Ginsenoside RG3 Synergizes With STING Agonist to Reverse Cisplatin Resistance in Gastric Cancer DOI Creative Commons
Zhongqi Lu, Yihang Fu, Qiang Fu

и другие.

Food Science & Nutrition, Год журнала: 2025, Номер 13(1)

Опубликована: Янв. 1, 2025

ABSTRACT This study investigates the synergistic inhibitory effects of combining stimulator interferon genes (STING) agonist cyclic diadenylate monophosphate (c‐di‐AMP) and ginsenoside RG3 on cisplatin (DDP)‐resistant gastric cancer (GC) cells. The objective is to identify novel therapeutic targets offers insights for clinical management DDP resistance. Various techniques were employed, including western blot, MTT assay, colony formation scratch transwell tubule flow cytometry, Hoechst 33342 fluorescence staining, in vivo experiments, investigate potential mechanisms combined application STING reversing resistance cancer. combination markedly suppressed key malignant behaviors, proliferation, migration, invasion, angiogenesis SGC‐7901/DDP Additionally, this treatment inhibited epithelial‐mesenchymal transition (EMT) process stem cell‐like characteristics cells, while downregulating expression resistance‐related proteins. effectively suppresses growth proliferation Ginsenoside RG3, well‐documented its multifaceted properties, antioxidant, anti‐aging, anti‐cancer effects, widely used managing chemotherapy‐related side effects. Furthermore, enhances anti‐tumor immunity by regulating signal transduction. comprehensively evaluated efficacy through vitro demonstrating significant inhibition progression reversal drug These findings offer a robust theoretical foundation applications highlight new future research.

Язык: Английский

Процитировано

0

Comparative Evaluation of Volumetric-Modulated Arc Therapy and Intensity-Modulated Radiotherapy in Postoperative Breast Cancer Treatment DOI Creative Commons
Lei Zhang,

Dandan Ji,

Xiaomei Huang

и другие.

British Journal of Hospital Medicine, Год журнала: 2025, Номер unknown, С. 1 - 19

Опубликована: Март 25, 2025

Aims/Background Breast cancer (BC) is one of the most prevalent malignancies among women globally, with postoperative radiotherapy playing a pivotal role in its multidisciplinary management. Volumetric-modulated arc therapy (VMAT) and intensity-modulated (IMRT) are advanced techniques that improve dose distribution uniformity within target volume while minimizing damage to surrounding normal tissues. This study aimed compare effects VMAT IMRT on immune function prognosis BC patients, providing scientific basis for clinical decision-making optimizing treatment strategies. Methods Between January 2022 2024, 265 patients who underwent or at Nantong First People’s Hospital were retrospectively analyzed. Based technique, categorized into group (129 cases) (136 cases). The efficacies 2 compared by assessing overall effectiveness, levels biomarkers, factors, quality life incidence adverse reactions. Results objective response rate (ORR) disease control (DCR) significantly higher (75.97% 93.80%, respectively) (63.24% 86.03%, respectively, p < 0.05). Serum antigen 15-3 (CA15-3), human epidermal growth factor receptor (HER2), carcinoembryonic (CEA), interleukin-6 (IL-6) decreased both groups 1-, 3-, 6-month post-radiotherapy immediately after (p Conversely, interleukin-2 (IL-2) interferon-α (IFN-α) demonstrated significant increase over same time points Notably, 1-month post-radiotherapy, exhibited lower serum CA15-3, HER2, CEA, IL-6 IL-2 IFN-α Post-radiotherapy, (QoL) scores encompassing mental health, physical environmental conditions, social relationships improved pre-radiotherapy However, no statistically differences QoL observed between two > reactions was (9.30%) (19.12%) Conclusion effectively marker profiles, modulate enhance patients. superior efficacy, achieving ORR DCR reduction radiotherapy-related IMRT. These findings highlight advantages comprehensive treatment.

Язык: Английский

Процитировано

0

Selective BCL-2 inhibitor triggers STING-dependent antitumor immunity via inducing mtDNA release DOI Creative Commons
Wenxin Zhang, Xiaohui Pan, Longsheng Wang

и другие.

Journal for ImmunoTherapy of Cancer, Год журнала: 2025, Номер 13(4), С. e010889 - e010889

Опубликована: Апрель 1, 2025

Background The stimulator of interferon genes (STING) signaling pathway has been demonstrated to propagate the cancer-immunity cycle and remodel tumor microenvironment emerged as an appealing target for cancer immunotherapy. Interest in STING agonist development increased, candidates hold significant promise; however, most are still early stages human clinical trials. We found that ABT-199 activated enhance immunotherapeutic effect, provided a ready-to-use small molecule drug activation. Methods Phosphorylation STING, TBK1, IRF3, well activation interferon-I (IFN-I) pathway, were detected following treatment various colorectal cells. C57BL/6J BALB/c mice with subcutaneous tumors employed evaluate vivo therapeutic effects anti-PD-L1 combination. Flow cytometry ELISA analyze level activity tumor-infiltrating T lymphocytes. Immunofluorescence quantitative real-time PCR conducted assess source accumulation double stranded DNA (dsDNA) cytoplasm. Chemical cross-linking assay, co-immunoprecipitation, CRISPR/Cas9-mediated knockout performed investigate molecular mechanism underlying ABT-199-induced voltage-dependent anion channel protein 1 (VDAC1) oligomerization mitochondrial (mtDNA) release. Results significantly cells, which was evidenced by increased phosphorylation TBK1 upregulation C-C motif chemokine ligand 5 (CCL5), C-X-C 10 (CXCL10), beta transcription. By promoting expression cytotoxic T-cell infiltration, promoted antitumor immunity synergized therapy improve efficacy. induced mtDNA cytoplasm triggered via canonical pathway. cGAS or STING-KO models abolished both efficacy ABT-199. Mechanically, VDAC1 disturbing binding between BCL-2 VDAC1, thereby facilitating release into ABT-199-triggered attenuated when VADC1 knocked out. Consistently, effect absence VDAC1. Conclusions Our results identify compound activation, reveal through activates provide theoretical basis use

Язык: Английский

Процитировано

0

Exploring the Anticancer Potential of Lamivudine-Loaded Polymeric Nanoparticles: In Vitro Cytotoxicity, Tissue Deposition, Biochemical Impact In Vivo, and Molecular Simulations Analysis DOI Creative Commons
Natália Cristina Gomes-da-Silva, Adiel Teixeira de Almeida, Patrícia Severino

и другие.

ACS Applied Bio Materials, Год журнала: 2025, Номер unknown

Опубликована: Май 19, 2025

Lamivudine is a synthetic nucleoside analogue to cytosine with modified sugar moiety. It has potent action against Human Immunodeficiency Virus and chronic hepatitis. Recently, studies have also shown that lamivudine (3TC) can induce apoptosis in cancer cells inhibit their proliferation, including breast cancer. We prepared polymeric nanoparticles using the double emulsification technique incorporate polycaprolactone (PCL) as polymer active compound. The were characterized by atomic force microscopy dynamic light scattering. Then we carried out full set of vitro vivo analyses, measurement cytotoxicity, radiolabeling, biodistribution biochemistry. results showed formation 273 nm spherical monodisperse behavior (PDI = 0.052). radiolabeling 99mTc demonstrated feasibility direct process. cytotoxicity corroborated potential triple-negative line (MDA-MB-231). assay revealed high uptake liver, small large intestines bladder, besides presence urine. biochemistry analysis alterations some enzyme levels, including: alanine aminotransferase (ALT), aspartate (AST), gamma GT (GGT), creatinine (CRE), amylase (MAS), lactate dehydrogenase pyruvate (LDH-P) glucose (GLU). Finally, performed theoretical molecular docking, dynamics interactions between key proteins regulating necroptosis, epidermal growth factor receptor (EGFR), receptor-interacting protein kinase 1 (RIPK1), 3 (RIPK3). Theoretical lamivudine's adaptability binding sites these proteins, for optimization enhance hydrophobic affinity. findings efficacy cells, need better understand interplay nanosystems biochemical parameters.

Язык: Английский

Процитировано

0

In Silico Discovery of Multi-Target Small Molecules and Efficient siRNA Design to Overcome Drug Resistance in Breast Cancer via Local Therapy DOI

Seyed Mohammad Javad Hashemi,

Hossein Ghalehnoei, Ali Barzegar

и другие.

Journal of Molecular Graphics and Modelling, Год журнала: 2025, Номер 140, С. 109086 - 109086

Опубликована: Май 20, 2025

Язык: Английский

Процитировано

0

Immune Cell Contribution to Mammary Gland Development DOI Creative Commons
Ramiah R. Vickers, Weston W. Porter

Journal of Mammary Gland Biology and Neoplasia, Год журнала: 2024, Номер 29(1)

Опубликована: Авг. 23, 2024

Abstract Postpartum breast cancer (PPBC) is a unique subset of cancer, accounting for nearly half the women diagnosed during their postpartum years. Mammary gland involution widely regarded as being key orchestrator in initiation and progression PPBC due to its wound-healing inflammatory signature. Here, we provide dialogue suggestive that lactation may also facilitate neoplastic development result sterile inflammation. Immune cells are involved all stages postnatal mammary development. It has been proposed functions these immune partially directed by epithelial (MECs) cytokines they produce. This suggests more niche area exploration aimed at assessing activation innate pathways within MECs could insight into cell contributions developing gland. contribution pubertal extensively studied; however, investigations pregnancy remain limited. During pregnancy, undergoes dramatic expansion prepare lactation. As result, susceptible replicative stress. lactation, mitochondria pushed capacity fulfill high energetic demands producing milk. metabolic stress, if unresolved, can elicit differentiating MECs. In this review, broadly discuss current knowledge each developmental stage, while emphasizing study will be beneficial discovery novel therapeutic biomarkers PPBC.

Язык: Английский

Процитировано

2

Ginseng extract (Ginsenoside RG3) combined with STING agonist reverses TAM/M2 polarization to inhibit TNBC evolution DOI Creative Commons
Qiang Fu, Zhongqi Lu, Ying Chang

и другие.

Industrial Crops and Products, Год журнала: 2024, Номер 222, С. 119589 - 119589

Опубликована: Сен. 9, 2024

Язык: Английский

Процитировано

2